Downstream targets of PKCβII in dendritic cell differentiation (66.4)

Abstract

Abstract Dendritic cells (DC) are antigen presenting cells, inducing both innate and adaptive immune responses. In a tumor setting their differentiation from progenitor cells is inhibited by tumor derived factors, resulting in an accumulation of immature DCs. When myeloid-derived DC differentiation is inhibited, these immature DCs act as myeloid derived suppressor cells (MDSCs) which support tumor growth and metastasis, as well as reduce efficacy of many therapeutic agents in cancer. Our lab has shown in humans that loss of PKCβII (a member of the PKC family of signal transduction molecules) expression blocks DC differentiation and that tumors may mediate this downregulation. It is also known that interferon regulatory factor 8 (IRF8) plays an important role myeloid cell differentiation from progenitor cells, and it is downregulated in tumor environments, inhibiting DC differentiation. In human and murine models, we determined that inhibition of PKCβII with CGP 53353 prevented differentiation of lineage negative progenitor cells to DCs as evaluated by DC phenotypic markers and allogeneic T-cell induction. We also found that PKCβII inhibition lead to a loss in IRF8 expression. Therefore we have demonstrated a role for PKCβII in DC differentiation in mice, as well as identified a line between IRF8 and PKCβII signaling during differentiation.